# Role of dentate granule cell glucocorticoid receptors in neuronal excitability and status epilepticus

> **NIH NIH F31** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $38,977

## Abstract

PROJECT SUMMARY/ABSTRACT
Patients in status epilepticus present with continuous seizures that are life-threatening without successful and
emergent seizure termination. Despite the fact that current therapies fail to stop seizures in 20% of patients,
physicians have relied on essentially the same treatment strategy for SE for almost 50 years: anti-seizure drugs,
such as benzodiazepines and other anti-convulsive agents. When treatment fails, patients enter refractory SE
for which the mortality rate can reach 60%. Not only is SE a medical emergency with a high mortality rate,
survivors are often left with irreversible and lasting brain damage. After a single episode of SE, almost half of
patients will develop spontaneous recurrent seizures and temporal lobe epilepsy. Further, psychiatric
comorbidities, such as anxiety and depression, are highly associated with the chronic epileptic state. Therefore,
to reduce both mortality and morbidity, it is imperative to elucidate the underlying mechanisms that drive the
severity and consequences of SE.
As a life-threatening stressor, SE results in robust activation of the hypothalamic-pituitary-adrenal axis and stress
hormone (i.e., glucocorticoid) release. Multiple lines of evidence suggest that glucocorticoids can increase
neuronal excitability under basal conditions and exacerbate excitotoxic injury under pathological conditions. In
fact, we have shown that giving exogenous glucocorticoids to epileptic rodents makes seizures worse. However,
exactly which brain regions or cell types mediate this effect is unknown. Here, I hypothesize that glucocorticoids
worsen status epilepticus severity by increasing the excitability of hippocampal dentate granule cells. In the
seizure-free brain, dentate granule cells limit or “gate” the amount of excitatory activity that can enter the
hippocampus, thereby preventing the propagation of seizures. Dentate granule cells are rich in glucocorticoid
receptor expression; therefore, if glucocorticoids increase dentate granule cell excitability, this gating function is
likely to fail during SE, allowing seizures to grow and spread.
To test my hypothesis, I have optimized a viral-mediated strategy to selectively delete glucocorticoid receptors
from hippocampal dentate granule cells prior to pilocarpine-induced SE. Using this approach, I will determine
whether glucocorticoid receptor deletion 1) decreases status epilepticus severity (Aim 1) and/or 2) decreases
dentate granule cell excitability (Aim 2). These studies will reveal whether glucocorticoid receptor-mediated
failure of the dentate gate plays a role in exacerbating status epilepticus-induced injury to the hippocampus.

## Key facts

- **NIH application ID:** 10234791
- **Project number:** 1F31NS122484-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Kimberly Lynn Kraus
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,977
- **Award type:** 1
- **Project period:** 2021-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10234791

## Citation

> US National Institutes of Health, RePORTER application 10234791, Role of dentate granule cell glucocorticoid receptors in neuronal excitability and status epilepticus (1F31NS122484-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10234791. Licensed CC0.

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